Onset Of Epilepsy Research Articles

Long-term effectiveness and tolerability of ketogenic diet therapy in patients with genetic developmental and epileptic encephalopathy onset within the first 6 months of life.

To investigate the effectiveness and tolerability of ketogenic diet therapy (KDT) in patients with developmental and epileptic encephalopathy (DEE) associated with genetic etiology which onset within the first 6 months of life, and to explore the association between response to KDT and genotype/clinical parameters. We retrospectively reviewed data from patients with genetic DEE who started KDT at Beijing Children's Hospital between January 1, 2016, and December 31, 2021. A total of 32 patients were included, involving 14 pathogenic or likely pathogenic single genes, and 16 (50.0%) patients had sodium/potassium channel gene variants. The median age at onset of epilepsy was 1.0 (IQR: 0.1, 3.0) months. The median age at initiation of KDT was 10.0 (IQR: 5.3, 13.8) months and the median duration of maintenance was 14.0 (IQR: 7.0, 26.5) months, with a mean blood β-hydroxybutyrate of 2.49 ± 0.62 mmol/L. During the maintenance period of KDT, 26 (81.3%) patients had a ≥50% reduction of seizure frequency, of which 12 (37.5%) patients achieved seizure freedom. Better responses were observed in patients with STXBP1 variants, with four out of five patients achieving seizure freedom. There were no statistically differences in the age of onset, duration of epilepsy before KDT, blood ketone values, or the presence of ion channel gene variants between the seizure-free patients and the others. The most common adverse effects were gastrointestinal side effects, which occurred in 21 patients (65.6%), but all were mild and easily corrected. Only one patient discontinued KDT due to nephrolithiasis. KDT is effective in treating early onset genetic DEE, and no statistically significant relationship has been found between genotype and effectiveness in this study. KDT is well tolerated in most young patients, with mild and reversible gastrointestinal side effects being the most common, but usually not the reason to discontinue KDT. This study evaluated the response and side effects of ketogenic diet therapy (KDT) in patients who had seizures within the first 6 months of life, and were diagnosed with genetic developmental and epileptic encephalopathy (DEE), a type of severe epilepsy with developmental delay caused by gene variants. Thirty-two patients involving 14 gene variants who started KDT at Beijing Children's Hospital between were included. KDT was effective in treating early onset genetic DEE in this cohort, and patients with STXBP1 variants responded better; however, no statistically significant relationship was found between gene variant and response. Most young patients tolerated KDT well, with mild and reversible gastrointestinal side effects being the most common.

Late infantile epileptic encephalopathy: A distinct developmental and epileptic encephalopathy syndrome.

Within the spectrum of developmental and epileptic encephalopathy (DEE), there are a group of infants with features that are distinct from the well-recognized syndromes of early infantile developmental and epileptic encephalopathy (EIDEE), infantile epileptic spasm syndrome (IESS), and Lennox-Gastaut syndrome (LGS). We refer to this condition as late infantile epileptic encephalopathy (LIEE). Our objective was to highlight the characteristics of this group by analyzing patients who exhibit prototypical features. From July 2022 to May 2023, we searched for LIEE features in pediatric patients who underwent epilepsy follow-up at the University of Chicago Comer Children's Hospital. Out of 850 patients evaluated, thirty patients (3.5%) were identified with LIEE based on electroclinical characteristics. These patients had an average onset of epilepsy at 6.8 months and an average onset of LIEE features at 18.1 months. The epilepsy etiology was most commonly genetic and metabolic (50%), followed by congenital cortical malformations (23%), acquired structural abnormalities (20%), and unknown (7%). The predominant seizure types were myoclonic-tonic (70%), spasm-tonic (50%), epileptic spasms (47%), tonic (43%), and myoclonic (43%) seizures. All patients reported a history of either spasm-tonic or myoclonic-tonic seizures in addition to other types. All patients had EEGs showing discontinuity, electrodecrements, or both along with diffuse slowing, background voltages between 100 and 300 μV, and superimposed multifocal, diffuse epileptiform discharges. Every patient, except one, fulfilled the definition of drug-resistant epilepsy, and all reported either moderate-to-severe or severe developmental delay. Late infantile epileptic encephalopathy (LIEE) is characterized by several unique clinical and electrographic features. Typically, LIEE manifests in patients during the second year of life and occurs before two years of age, hence late infantile onset. The condition is commonly observed in infants with symptomatic epilepsy. Myoclonic-tonic and spasm-tonic seizures are the quintessential seizure types. The inter-ictal EEG exhibits more organization and lower voltages than seen with hypsarrhythmia and lacks the defining EEG characteristics of EIDEE, IESS, or LGS. We propose that LIEE is a distinct electroclinical syndrome within the spectrum of developmental and epileptic encephalopathies.

Impact of prenatal, neonatal, and postnatal factors on epilepsy risk in children and adolescents: a systematic review and meta-analysis

Abstract Background Epilepsy is a common, long-term neurological condition. Several previous case-control, cohort and cross-sectional studies have highlighted the role of prenatal, delivery and postnatal factors in the onset of epilepsy. In this systematic review, we evaluate the impact of these factors on the development of epilepsy in children and adolescents. Methods We searched PubMed and Google Scholar for literature on the relationship between prenatal, delivery and postnatal factors and the occurrence of epilepsy. The research was performed according to the PRSIMA 2020 flowchart and checklist. Data were extracted and pooled according to the ReviewManager 5.3 software using a random-effects model. Sensitivity analysis and subgroup analysis were used to evaluate the source of heterogeneity. Results We identified 25 reports, including 45,044 cases with confirmed epilepsy and 2,558,210 controls. Premature birth is significantly associated with the risk of epilepsy (pooled OR = 4.36 [95% CI: 1.26–15.09], P = 0.02). Smoking during pregnancy significantly increases this risk by 28% (pooled OR = 1.28 [95% CI:1.1–1.49], P = 0.002). Furthermore, maternal epilepsy confers a pooled OR of 2.06 [95% CI:1.26–3.36]. Eclampsia is linked to a 16.9-fold increased risk of epilepsy. In addition, both pregnancy metrorrhagia and maternal infection are significantly associated with the epilepsy risk (pooled OR = 2.24 [95% CI: 1.36–3.71] and 1.28 [95% CI: 1.17–1.41], respectively). For delivery conditions, cord prolapse (pooled OR = 2.58 [95% CI: 1.25–5.32]), prolonged labor (> 6 h) (OR = 6.74 [95% CI: 3.57–12.71]) and head trauma (pooled OR = 2.31 [95% CI: 1.54–3.48]) represent a meaningful risk of epilepsy occurrence. Moreover, birth complications (OR = 3.91 [95% CI: 2.43–6.29]), low birth weight (pooled OR = 1.83 [95% CI: 1.5–2.23]) and male birth (pooled OR = 1.18 [95% CI: 1.06–1.32]) are associated with an elevated risk of epilepsy in childhood and adolescence. Conclusions Epilepsy in children and adolescents can be attributed to a multitude of intricate factors, notably those during pregnancy, delivery and the postnatal period. These findings highlight the crucial role of prenatal and postnatal care in reducing the impact of these factors on epilepsy occurrence.

Long-term follow-up of adult patients with serial and status course of epileptic seizures

To study the follow-up of adult patients with status epilepticus or a history of serial seizures, assessing the likelihood of achieving long-term remission and identifying predictors of treatment effectiveness. The study included 280 patients divided into 137 patients with epilepsy with a series of seizures or a history of status epilepticus (group 1) and 143 patients, who had not previously received therapy and did not have a series of seizures or a history of status epilepticus (group 2). A clinical and neurological examination, analysis of medical documentation data, electroencephalography, and MRI were performed. After correction of therapy, remission in patients in group 1 was achieved in 21.9%, improvement in 30%, no effect was observed in 48.1%; in group 2 the indicators were 51%, 28.7%, 20.3%, respectively. The onset of epilepsy in childhood, frequent seizures, and regional epileptiform activity were associated with the lack of treatment effect. The results confirm the main role of the clinical examination in determining the prognosis of epilepsy in a particular patient. Currently available instrumental techniques have limited predictive value.

Risk Assessment Tool in Predicting the Therapeutic Outcomes of Antiseizure Medication in Adults with Epilepsy.

Identifying a patient's risk for poor outcomes after starting antiseizure medication (ASM) therapy is crucial in managing epilepsy pharmacologically. To date, there is a lack of designated tools to assess such risks. To develop and validate a risk assessment tool for the therapeutic outcomes of ASM therapy. A cross-sectional study was carried out in a hospital-based specialist clinic from September 2022 to August 2023. Data was analyzed from patients' medical records and face-to-face assessments. The seizure control domain was determined from the patients' medical records while seizure severity (SS) and adverse effects (AE) of ASM were assessed using the Seizure Severity Questionnaire and the Liverpool Adverse Event Profile respectively. The developed tool was devised from prediction models using logistic and linear regressions. Concurrent validity and interrater reliability methods were employed for validity assessments. A total of 397 patients were included in the analysis. For seizure control, the identified predictors include ≥10 years' epilepsy duration (OR:1.87,95% CI:1.10-3.17), generalized onset (OR:7.42,95% CI:2.95-18.66), focal onset seizure (OR:8.24,95% CI:2.98-22.77), non-adherence (OR:3.55,95% CI:1.52-8.27) and having ≥3 ASM (OR:3.29,95% CI:1.32-8.24). Younger age at epilepsy onset (≤40) (OR:3.29,95% CI:1.32-8.24) and neurological deficit (OR:3.55,95% CI:1.52-8.27) were significant predictors for SS. For AE, the positive predictors were age >35 (OR:0.12,95% CI:0.03-0.20), <13 years epilepsy duration (OR:2.89,95% CI:0.50-5.29) and changes in ASM regimen (OR:2.93,95% CI: 0.24-5.62). The seizure control domain showed a good discriminatory ability with a c-index of 0.711. From the Bonferroni (ANOVA) analysis, only SS predicted scores generated a linear plot against the mean of the actual scores. The AE domain was omitted from the final tool because it did not meet the requirements for validity assessment. This newly developed tool (RAS-TO) is a promising tool that could help healthcare providers in determining optimal treatment strategies for adults with epilepsy.

Comparative study of epilepsy registry system in America, England, Australia, and Iran.

Disease registries are one of the important steps in the development of health information systems. The aim of this study was to compare epilepsy registration systems in the United States, England, and Australia and propose a National Epilepsy Registry System for Iran. This study was a descriptive-comparative study conducted between 2020 and 2023, which involved the following steps: identification and selected countries with advanced registry systems in the world and Identification of their characteristics and comparison with each other. The research population included the epilepsy registration registry in Australia, England, the United States, and Iran. In this study, data were collected from forms, observations, and documents. In Australia, all databases, reports, and minimum datasets are electronically sent to the Australian Epilepsy Register. In England, the Epilepsy Society is responsible for collecting information. In the United States, all individuals with epilepsy voluntarily send their information to registry centers and the Epilepsy Society to help with their treatment. However, there is no national epilepsy registry system in Iran. Therefore, recommendations have been made to establish. Registration systems can help collect and analyze data related to all patients with a particular disease. When this registration is established at the national level, it becomes a valuable clinical tool for improving the quality of care and can be a significant step toward managing care for epilepsy patients and healthcare centers. Indeed, such a system can also help in preventing the onset of epilepsy and planning for the improvement of the quality of life for patients.

Determinants of Depression among Adult Epileptic Patients, in Ayder Comprehensive Specialized Hospital and Mekelle General Hospital, Tigray, Ethiopia. Case Control Study

Background: Depression is one of the most prevalent psychiatric disorders occurring in patients with epilepsy. There are no studies that assessed the factors among epileptic people in Mekelle, Tigray, Ethiopia. Therefore, this study determined the factors of depression in people with epilepsy. Methods: Unmatched case control study was conducted from May 1 to 30, 2019 in Ayder Comprehensive Specialized Hospital and Mekelle General Hospital on 66 cases and 132 controls calculated using double population proportion formula. Study subjects were selected two controls after each case. Data were collected using a standardized and pretested questioner. Data was collected by four trained BSc nursing professionals under Psychiatric Nurse supervisor. Depression was measured by patient health questionnaire-nine using face to face interview techniques. Data were analyzed using SPSS 23. Result: This study revealed that being female (AOR=2.79, 95% CI: 1.08-7.18, P=0.03), living with relative (AOR=2.82,95% CI:1.12-7.18, P=0.03), seizure frequency four and above per month (AOR=6.00, 95% CI:1.39-25.86, P=0.02), age onset of epilepsy between 12-24 years of age (AOR=3.11, 95% CI: 1.06-9.18, P=0.04), poor social support (AOR=5.34, 95% CI: 2.13-13.41, P=0.00) were significantly associated with depression. Conclusion: Factor associated like gender (female), living status (with relative), poor social support, age onset of epilepsy (between 12 to 24 years) and seizure frequency are the factors associated with depression. Depression prevention efforts should be targeted towards these risk factors.

Neuropsychiatry revisited: epilepsy as the borderland between neurology and psychiatry.

Since epilepsy is often complicated by psychiatric symptoms, the contributions of psychiatry are indispensable for the care and improvement of the quality of life of individuals with epilepsy. Moreover, the existence of a bidirectional relationship between epilepsy and psychiatric symptoms was recently proposed, based on the evidence that not only are some psychiatric symptoms more likely than others to follow epilepsy, but also that psychiatric symptoms may precede the onset of epilepsy and the presence of psychiatric symptoms may influence the outcome of treatment for seizures. There has also been a gradual accumulation of neurobiological findings related to psychosis, depressive, and anxiety symptoms that are associated with epilepsy with respect to abnormalities in brain networks and neurotransmission. This mini-review focuses on the neuropsychiatric aspects of epilepsy and proposes that a reconsideration of neuropsychiatry in light of epilepsy findings could serve as a bridge between psychiatry and neurology.

Col4a2 Mutations Contribute to Infantile Epileptic Spasm Syndrome and Neuroinflammation.

There are more than 70 million people worldwide living with epilepsy, with most experiencing the onset of epilepsy in childhood. Despite the availability of more than 20 anti-seizure medications, approximately 30% of epilepsy patients continue to experience unsatisfactory treatment outcomes. This situation places a heavy burden on patients' families and society. Childhood epilepsy is a significant chronic neurological disease that is closely related to genetics. Col4a2, the gene encoding the α2 chain of type IV collagen, is known to be associated with multiple diseases due to missense mutations. The Col4a2 variant of collagen type IV is associated with various phenotypes, including prenatal and neonatal intracranial hemorrhage, porencephaly, porencephaly with cataracts, focal cortical dysplasia, schizencephaly, strokes in childhood and adolescence, and sporadic delayed hemorrhagic stroke. Although epilepsy is recognized as a clinical manifestation of porencephaly, the specific mechanism of Col4a2-related epileptic phenotypes remains unclear. A total of 8 patients aged 2 years and 2 months to 18 years who were diagnosed with Col4a2-related infantile epileptic spasm syndrome were analyzed. The seizure onset age ranged from 3 to 10 months. Initial EEG results revealed hypsarrhythmia or multiple and multifocal sharp waves, spike waves, sharp slow waves, or spike slow waves. Elevated levels of the cytokines IL-1β (32.23±12.58 pg/ml) and IL-6 (45.12±16.03 pg/ml) were detected in the cerebrospinal fluid of these patients without any signs of infection. Following antiseizure treatment, decreased IL-1β and IL-6 levels in the cerebrospinal fluid were noted when seizures were under control. Furthermore, we aimed to investigate the role of Col4a2 mutations in the development of epilepsy. Through the use of immunofluorescence assays, ELISA, and Western blotting, we examined astrocyte activity and the expression of inflammatory cytokines such as IL-1β, IL-6, and TNF-α after overexpressing an unreported Col4a2 (c.1838G>T) mutant in CTX-TNA cells and primary astrocytes. We found that the levels of the inflammatory factors IL-1β, IL-6, and TNF-α were increased in both CTX-TNA cells (ELISA: p = 0.0087, p<0.001, p<0.001, respectively) and primary astrocytes (ELISA: p = 0.0275, p<0.001, p<0.001, respectively). Additionally, we conducted a preliminary investigation of the role of the JAK/STAT pathway in Col4a2 mutation-associated epilepsy. Col4a2 mutation stimulated astrocyte activation, increasing iNOS, COX-2, IL-1β, IL-6, and TNF-α levels in both CTX-TNA cells and primary astrocytes. This mutation also activated the JAK/STAT signaling pathway, leading to increased phosphorylation of JAK2 and STAT3. Treatment with the JAK/STAT inhibitor WP1066 effectively counteracted this effect in primary astrocytes and CTX-TNA cells. To date, the genes who mutations are known to cause developmental and epileptic encephalopathies (DEEs) are predominantly grouped into six subtypes according to function. Our study revealed that an unreported mutation site Col4a2Mut (c.1838G>T) of which can cause neuroinflammation, may be a type VII DEE-causing gene.

Diagnosis, epilepsy treatment and supports for neurodevelopment in children with Dravet Syndrome: Caregiver reported experiences and needs

BackgroundDravet syndrome is a rare infantile onset epilepsy syndrome encompassing treatment resistant epilepsy and neurodevelopmental difficulties. There is limited data regarding caregiver experiences of diagnosis, treatment and supports for the associated neurodevelopmental problems. MethodSemi-structured interviews were conducted with caregivers of 36/48 children (75% of total population in Sweden) with Dravet syndrome. Data was analysed using thematic analysis. ResultsRegarding the diagnostic experience, themes were: Delays in diagnostic process, genetic testing not optimal, communication of Dravet syndrome diagnosis and support and information soon after diagnosis. Caregivers felt that delays in diagnosis and testing could have been avoided whilst experiences of communication of diagnosis and support after diagnosis varied. In terms of treatment for seizures, the themes were: Satisfied with treatment, emergency treatment, treatment with antiseizure medications, strategies to control seizures via temperature regulation/avoidance of infections and use of equipment and aids. Caregivers were in the main accepting that seizures in Dravet syndrome are very difficult to treat and that seizure freedom is often an unachievable goal. Many felt frustrated that they were expected to take responsibility with respect to choice of medication. They often employed strategies (e.g., avoidance of physical activity) to reduce seizures or their impact. In terms of supports for neurodevelopmental problems, the themes were: Struggled to access support, lack of integrated healthcare and satisfaction with school. Many caregivers felt that accessing necessary supports for their children and developmental and behavioural needs was a struggle and that the provision of support often lacked integration e.g., lack of collaboration between child’s disability service and school. Caregivers also expressed a desire that there would be better knowledge of Dravet syndrome in emergency departments and schools, that care would be better integrated and that there would be more supports for assessment and interventions regarding the associated neurodevelopmental problems. ConclusionThe responses of caregivers of children with Dravet syndrome highlight the need for supports from diagnosis for both epilepsy and neurodevelopmental problems. Good examples of provision were identified but parents often felt they lacked support and support often came from providers who lacked knowledge of the syndrome. Collaboration between medical, disability and school services was often lacking.

Distinctive In Vitro Phenotypes in iPSC-Derived Neurons From Patients With Gain- and Loss-of-Function SCN2A Developmental and Epileptic Encephalopathy.

SCN2A encodes NaV1.2, an excitatory neuron voltage-gated sodium channel and a major monogenic cause of neurodevelopmental disorders, including developmental and epileptic encephalopathies (DEE) and autism. Clinical presentation and pharmocosensitivity vary with the nature of SCN2A variant dysfunction and can be divided into gain-of-function (GoF) cases with pre- or peri-natal seizures and loss-of-function (LoF) patients typically having infantile spasms after 6 months of age. We established and assessed patient induced pluripotent stem cell (iPSC) - derived neuronal models for two recurrent SCN2A DEE variants with GoF R1882Q and LoF R853Q associated with early- and late-onset DEE, respectively. Two male patient-derived iPSC isogenic pairs were differentiated using Neurogenin-2 overexpression yielding populations of cortical-like glutamatergic neurons. Functional properties were assessed using patch clamp and multielectrode array recordings and transcriptomic profiles obtained with total mRNA sequencing after 2-4 weeks in culture. At 3 weeks of differentiation, increased neuronal activity at cellular and network levels was observed for R1882Q iPSC-derived neurons. In contrast, R853Q neurons showed only subtle changes in excitability after 4 weeks and an overall reduced network activity after 7 weeks in vitro. Consistent with the reported efficacy in some GoF SCN2A patients, phenytoin (sodium channel blocker) reduced the excitability of neurons to the control levels in R1882Q neuronal cultures. Transcriptomic alterations in neurons were detected for each variant and convergent pathways suggested potential shared mechanisms underlying SCN2A DEE. In summary, patient iPSC-derived neuronal models of SCN2A GoF and LoF pathogenic variants causing DEE show specific functional and transcriptomic in vitro phenotypes.

Reproducible network changes occur in a mouse model of temporal lobe epilepsy but do not correlate with disease severity

Studying the development of brain network disruptions in epilepsy is challenged by the paucity of data before epilepsy onset. Here, we used the unilateral, kainate mouse model of hippocampal epilepsy to investigate brain network changes before and after epilepsy onset and their stability across time.Using 32 epicranial electrodes distributed over the mouse hemispheres, we analyzed EEG epochs free from epileptic activity in 15 animals before and 28 days after hippocampal injection (group 1) and in 20 animals on two consecutive days (d28 and d29, group 2). Statistical dependencies between electrodes were characterized with the debiased-weighted phase lag index. We analyzed: a) graph metric changes from baseline to chronic stage (d28) in group 1; b) their reliability across d28 and d29, in group 2; c) their correlation with epileptic activity (EA: seizure, spike and fast-ripple rates), averaged over d28 and d29, in group 2.During the chronic stage, intra-hemispheric connections of the non-injected hemisphere strengthened, yielding an asymmetrical network in low (4–8 Hz) and high theta (8–12 Hz) bands. The contralateral hemisphere also became more integrated and segregated within the high theta band. Both network topology and EEG markers of EA were stable over consecutive days but not correlated with each other.Altogether, we show reproducible large-scale network modifications after the development of focal epilepsy. These modifications are mostly specific to the non-injected hemisphere. The absence of correlation with epileptic activity does not allow to specifically ascribe these network changes to mechanisms supporting EA or rather compensatory inhibition but supports the notion that epilepsy extends beyond the sole repetition of EA and impacts network that might not be involved in EA generation.

Epilepsy in childhood and school performance: a nation-wide cohort study.

Childhood epilepsy has been linked to poor academic performance, but large-scale studies are lacking. In this nation-wide study of school-aged children, we examined the association between childhood epilepsy and school performance in standardized tests according to phenotypic and treatment-related characteristics. We performed a matched register-based cohort study of children born in Denmark (1997-2009) who participated in the Danish National School Test Programme between 2010 and 2019. We used population and health registers to identify children with epilepsy and a randomly sampled sex- and age-matched reference cohort without epilepsy (ratio 1:10). Norm-based test scores from language and mathematics reflecting performance as a percentile of the nation-wide distribution of scores (scale 1-100) were used to assess academic performance. Adjusted differences in mean standardized scores between children with and without epilepsy were estimated using linear regression models. Among 582 840 children participating in the School Test Programme, we identified 4659 (0.8%) children with epilepsy (52.8% males) and 46 590 matched reference children. Median age at epilepsy onset was 7.5 years (interquartile range: 4.0-10.6). Childhood epilepsy was associated with poorer school performance overall (mean score = 48.2 versus references = 56.7; adjusted difference = -6.7, 95% CI: -7.4 to -6.0), and worse performance was found in all epilepsy subgroups, including in 3534 children with uncomplicated epilepsy (i.e. no other pre-existing neurologic or intellectual disabilities and no identified possible cause for epilepsy; adjusted difference = -6.0, 95% CI: -6.8 to -5.2). No major variation by sex, age or subject was observed, but larger score differences were seen in children using antiseizure medication at time of testing (e.g. valproate monotherapy, adjusted difference = -9.3, 95% CI: -11.5 to -7.0 and lamotrigine monotherapy, adjusted difference = -13.1, 95% CI: -15.0 to -11.3) and in children with psychiatric comorbidity, especially epilepsy with comorbid intellectual disability (adjusted difference = -27.0, 95% CI: -30.0 to -23.9) and epilepsy with comorbid attention deficit/hyperactivity disorder (adjusted difference = -15.7, 95% CI: -19.0 to -12.4). Children with epilepsy scored significantly lower than their unaffected siblings (adjusted difference = -6.2, 95% CI: -7.1 to -5.4). In conclusion, childhood epilepsy was associated with impaired academic performance throughout schooling, which suggest that there is a widespread need for educational support of children with epilepsy, even when the child has no other comorbidities and when the epilepsy appears well-managed.

Pharmacological impact on the expression of microglial and astroglial proteins involved in the regulation of epileptogenesis as a possible new strategy for epilepsy therapy

Pharmacological impact on the expression of microglial and astroglial proteins involved in the regulation of epileptogenesis as a possible new strategy for epilepsy therapy

Febrile seizures cause a decrease in calcium-permeable AMPA receptors at synapses of rat cortical and hippocampal pyramidal neurons

Febrile seizures (FS) are a prevalent childhood neurological disorder that can result in lasting functional alterations in neural networks, contributing to the onset of epilepsy and cognitive impairment [1]. Higher levels of calcium-permeable AMPA receptors (CP-AMPARs), which lack the GluA2 subunit, are detected in the hippocampus and cortex at an early age. CP-AMPARs are involved in various plastic changes within the central nervous system (CNS), including regular physiological processes (synaptic plasticity) and various pathological conditions. Such changes occur when these receptors are included in the neurons’ membrane, where they are not typically expressed. CP-AMPARs were demonstrated to incorporate into synapses during seizures [2]. The effect of FSs on CP-AMPAR expression is uncertain, and the resultant alterations in neuronal network function are unclear. The aim of this study was to determine whether the proportion of CP-AMPARs at synapses of pyramidal neurons in the rat entorhinal cortex and hippocampus alters immediately (at 15 min) and 48 h post FS. Ten-day-old rats were exposed to a stream of warm air (46 °C) for 30 minutes to induce hyperthermia, resulting in the development of FS. Only animals with FS that lasted for a minimum of 15 minutes were included in the study. The control group was comprised of littermates removed from the dam for an equivalent period but kept at room temperature. Isolated pyramidal neurons were used to determine the proportion of CP-AMPARs in the hippocampus. AMPAR-mediated currents were induced by application of 100 μM kainate. Excitatory postsynaptic currents (EPSCs) were evoked by extracellular stimulation in the entorhinal cortex. The antagonist IEM-1460 was used to selectively block CP-AMPARs. The rectification index of AMPA-mediated EPSCs was calculated to better assess the contribution of CP-AMPARs. Neurons expressing CP-AMPARs were visualized using the kainate-induced cobalt uptake method. Brain slices were stimulated with kainate while AR-5 and TTX were present. The DNQX blocker was used for the determination that the influx of Co2+ was mediated by AMPARs. Basal synaptic transmission was assessed by recording field postsynaptic responses in the hippocampus stimulated by Shaffer collaterals at different current strengths. FS induced a rapid decrease in the levels of CP-AMPARs on the membranes of pyramidal neurons in the hippocampus. As a result, 15 min after FS, IEM-1460 caused significantly less blockade of kainate-evoked current in neurons isolated from rat hippocampus compared to control (22% vs. 14%, p 0.05). A similar finding was observed for EPSCs evoked extracellularly in the entorhinal cortex, with a frequency of 10% in the FS group compared to 3% in the control group (p 0.05). Furthermore, the FS group’s neurons exhibited a significantly greater rectification index of EPSCs compared to the control group’s neurons. However, two days post-FS, no significant differences existed between the two groups. This observation may be attributed to the rapid decrease in the proportion of CP-AMPARs in pyramidal neurons at this stage. The cobalt uptake method supported electrophysiological findings, revealing higher staining levels in the CA1 field of the hippocampus and entorhinal cortex of control rats compared to FS rats. The observed effect surfaced 15 minutes after FS, and no divergences emerged between the groups after two days. Although the proportion of CP-AMPARs was reduced, basal neurotransmission levels in brain slices obtained from rats that underwent FS did not differ from control values. In summary, the expression of CP-AMPARs in entorhinal cortex and hippocampal pyramidal neurons in young rats decreases significantly with FS. These alterations do not impact the characteristics of basal synaptic transmission in the hippocampus.

Status epilepticus in patients with genetic generalized epilepsy: a case series study

BackgroundGenetic generalized epilepsy (GGE) accounts for nearly one-third of all epilepsies. The feature of status epilepticus (SE) in patients with GGE has been rarely studied. We aimed to determine the electroclinical characteristics of SE in patients with GGE.MethodsIn this retrospective study, nine patients with GGE were enrolled at Xijing Hospital, Xi’an, China from May 2014 to May 2020. SE was confirmed by 24-h video-EEG recording. The demography, clinical manifestation, brain MRI and SE pattern were analyzed.ResultsOf the nine patients in the study, seven were female. The mean age of the patients at the time of inclusion was 16.8 years (range 7–31 years), and the mean age at the onset of epilepsy was 10.9 years (range 6–17 years). The follow-up time ranged from 3 months to 6 years. Myoclonic absence status was identified in four patients showing eyelid myoclonia with absence and one patient showing perioral myoclonia with absences. Myoclonic SE was identified in three patients showing juvenile myoclonic epilepsy. Autonomic SE was found in one patient with eyelid myoclonia with absence. SE was terminated by oral midazolam in four patients. In the other five patients, SE terminated spontaneously.ConclusionsThe seizure type of SE in patients with GGE is often consistent with their major symptoms. Oral midazolam may be an option to terminate SE in patients with GGE.

10027-CBMS-3 POSTOPERATIVE EPILEPTOGENICITY IN GLIOBLASTOMA ARE ACHIEVED AS THE RESULT OF INTERACTIVE FLUCTUATIONS OF GLUTAMATE AND STEM CELL MARKER

Abstract BACKGROUND AND OBJECTIVE In our recent Glioblastoma multiforme (GBM) cases, postoperative epilepsy mostly occurred later than twenty-eight days after surgery. CD44, a stem cell marker, is known to relate with tumor cell invasiveness, however, little are known with epilepsy nor glutamate (Glu). We investigated the relationship between CD44 and the pathophysiology of this post operative late-phase epilepsy. MATERIALS AND METHODS A total of 10 GBM cases received surgery and postoperative treatment at our institute were divided into two groups; 4 cases of epilepsy onset, group E, and 6 cases without, group NE. In each group, the tumor was separated into core and periphery, from which Glu was measured (Amino Acid Analyzer L8900; Hitachi High-Tech Corporation) with expression of xCT, EAAT2 and CD44 examined (Western blot). The same objects were also examined on our three glioma stem-like cell (GSC) lines. In addition, we figured Factor X (F-X) as a key related factor, and evaluated the same objects on the GSCs under conditioned F-X (under submission). RESULTS Group E showed higher Glu than group NE both in the core and periphery. CD44 expression was significantly higher in group E in the periphery, and xCT was higher in group E both in the core and periphery. EAAT2 was lower in group E both in the core and periphery. Among the GSCs, GSC-2 had the highest CD44 expression while having the lowest xCT and extracellular Glu, and the highest EAAT2. In addition, CD44 knockdown in GSC-2 resulted in significant increase of xCT expression and extracellular Glu. Furthermore, changing the concentration of F-X low to high led to decreased expression of CD44 and increased xCT. CONCLUSION The postoperative epileptogenicity could be gained by the increase of Glu which results from the alterations of CD44, xCT and EAAT2. F-X could enhance the ability of Glu discharge.

Current state of hemispherectomy and callosotomy for pediatric refractory epilepsy in Denmark

ObjectiveTo evaluate outcomes from hemispherectomy and callosotomy related to the need for anti-seizure medication (ASM), seizure frequency, and cognition. MethodsA review of the medical charts of all Danish pediatric patients who underwent hemispherectomy or callosotomy from January 1996 to December 2019 for preoperative and postoperative ASM use, seizure frequency, and cognitive data. ResultsThe median age of epilepsy onset was two years (interquartile range (IQR): 0.0–5.3) for the hemispherectomy patients (n = 16) and one year (IQR: 0.6–1.7) for callosotomy patients (n = 5). Median time from onset to final surgery was 3.4 years for hemispherectomy and 10.2 years for callosotomy, while the median follow-up time was 6.9 years and 9.0 years, respectively. Preoperatively, all patients had daily seizures and were treated with ≥ 2 ASM. Hemispherectomy resulted in a reduction in seizure frequency in 87.5 % of patients, with 78.6 % achieving seizure freedom. Furthermore, 81.3 % experienced a reduction in ASM use and 56.3 % stopped all ASM. Median IQ/developmental quotient (IQ/DQ) was low preoperatively (44.0 [IQR: 40.0–55.0]) and remained unchanged postoperatively (IQ change: 0.0 [IQR: −10.0–+4.0]). Callosotomy resulted in a seizure reduction of 86–99 % in four patients, and ASM could be reduced in three patients. Median IQ/DQ was 20.0 preoperatively (IQR: 20.0–30.0) and remained unchanged postoperatively (IQ change: 0.0 [IQR: 0.0]). ConclusionHemispherectomy and callosotomy result in a substantial reduction in seizure frequency and ASM use without deterioration of IQ. Extensive epilepsy surgery should be considered early in children with drug-resistant epilepsy.

COGNITIVE IMPAIRMENT AFTER THE DIAGNOSIS OF LATE‐ONSET EPILEPSY ‐ A SYSTEMATIC REVIEW

AbstractBackgroundThe management of late‐onset epilepsy in older people (LOE) is often suboptimal despites its high incidence. The impact of LOE is not only epileptic, it also leads to multiple consequences, such as cognitive decline, and other geriatric syndromes. Cognitive decline, as one of the major consequences of LOE, causes in turn deterioration in quality of life and loss of autonomy. However, the effect of de novo LOE on cognitive decline without dementia in older people remains poorly understood. Similarly, very few studies have analysed the risk factors associated with cognitive decline. Therefore, we conducted a systematic review to describe the long‐term effect on cognition of LOE on older people, including the incidence of cognitive decline after the diagnosis of LOE and the associated risk factors.MethodAccording to PRISMA 2020 guidelines, we searched 5 electronic databases (“EMBASE”, “Medline”, “CINAHL”, “PsycINFO”, “Web of Science”) for articles published until 27th Oct 2022. The criteria selected were patients “60 years old and older” with “late onset epilepsy” diagnosis and “cognitive decline” or “cognitive impairment”, whom do not have known brain tumor or a posttraumatic etiology. Four researchers independently screened studies based on the title and abstract, then by full text. Data extraction was done through “Covidence” platform with each study being processed by two reviewers and conflicts were solved by a third reviewer.ResultWe selected 26 out of 326 initially retrieved publications based on full text review. Most of the studies conducted so far however did not take into consideration or did not control for the baseline cognitive status of their patients before or at the onset of epilepsy and therefore could not objectively determine the real burden of late onset epilepsy on cognitive impairment in this population.ConclusionData in favour of a causal relationship between late onset epilepsy and cognitive decline in elderly with no known baseline cognitive impairment is still precarious. More studies should be conducted with more specific assessment tools that could permit us to have a better estimate of the burden of LOE on cognition such for example imaging and neuropsychological assessment before and after the incidence of epilepsy.

Gender factors associated with the onset of drug-resistant epilepsy

Gender factors associated with the onset of drug-resistant epilepsy